A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways in Plasmodium vivax Hypnozoites.

Radical cure of Plasmodium vivax malaria must include elimination of quiescent 'hypnozoite' forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets for hypnozoites, we screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library and a collection of epigenetic inhibitors against P. vivax liver stages. From both libraries, we identified inhibitors targeting epigenetics pathways as selectively active against P. vivax and P. cynomolgi hypnozoites. These include DNA methyltransferase (DNMT) inhibitors as well as several inhibitors targeting histone post-translational modifications. Immunofluorescence staining of Plasmodium liver forms showed strong nuclear 5-methylcystosine signal, indicating liver stage parasite DNA is methylated. Using bisulfite sequencing, we mapped genomic DNA methylation in sporozoites, revealing DNA methylation signals in most coding genes. We also demonstrated that methylation level in proximal promoter regions as well as in the first exon of the genes may affect, at least partially, gene expression in P. vivax. The importance of selective inhibitors targeting epigenetic features on hypnozoites was validated using MMV019721, an acetyl-CoA synthetase inhibitor that affects histone acetylation and was previously reported as active against P. falciparum blood stages. In summary, our data indicate that several epigenetic mechanisms are likely modulating hypnozoite formation or persistence and provide an avenue for the discovery and development of improved radical cure antimalarials.

[From treatment to whole course management: envisioning comprehensive management of Talaromycosis marneffei].

Talaromycosis marneffei has been increasing in recent years. Our understanding of this disease has gradually deepened through extensive basic and clinical research, but there are still many limitations. In this article, by incorporating the latest research advancements, we discuss important issues in managing Talaromycosis marneffei trends, aiming to guide effective prevention and control of the disease, improving public health, and reducing the healthcare burden.

Hurricane Michael and Adverse Social and Mental Health Risk Factors.

OBJECTIVES: To assess changes in mental health and social risk factors in pregnant women in counties affected by Hurricane Michael (October 2018). METHODS: Data from the Universal Perinatal Risk Screen (UPRS) and vital statistics for the state of Florida were obtained. Prenatal risk factors (unplanned pregnancy, mental health services, high stress, use of tobacco or alcohol, young children at home or with special needs, trouble paying bills) were compared in the year before and year after Hurricane Michael in affected counties (n = 18,887). Log-Poisson regression with robust variance was used for binary outcomes, adjusting for maternal age, race, BMI, and education. RESULTS: A smaller proportion of pregnant women were screened in the months after the hurricane. No changes were seen in overall scores. The proportion referred was lower in the 1 month after Michael compared to that in 1 month before Michael (RR 0.78, 95% CI = 0.71, 0.86), but greater in the year after (RR = 1.07, 95% CI: 1.04, 1.10). Most individual risk factors on the screener did not change significantly, except having an illness that required ongoing medical care was less common in the short term (3 months after vs. 3 months before: aRR = 0.76, 95% CI: 0.66, 0.87), and more common in the longer term (1 year after vs. 1 year before, aRR = 1.09, 95% CI: 1.02, 1.18). Birth certificate data suggested smoking during pregnancy was higher among women who experienced Michael during their pregnancies (aRR = 1.15, 95% CI: 1.01, 1.32). DISCUSSION: Perinatal screening and referral declined in the short-term aftermath of Hurricane Michael.

[The correlation between reflux esophagitis and Helicobacter pylori infection based on natural population].

Objective: Reflux esophagitis (RE) may be negatively correlated with Helicobacter pylori (H. pylori) infection, but the conclusion and relevant mechanism is still controversial. This study proposed to explore the correlation between RE and H. pylori infection based on natural population. Methods: From July 2013 to December 2014, 3 940 residents aged 40-69 years were recruited in Linqu County of Shandong Province and Hua County of Henan Province by the whole sampling method. All the subjects underwent gastroscopy, and gastric mucosa biopsy specimens were collected for pathological diagnosis and Warthin-Starry (WS) staining to identify H. pylori infection. Venous blood samples of some subjects were collected for H. pylori immunoglobulin G (H. pylori-IgG) detection. Also, demographic and sociological data were collected. Chi-square test and logistic regression were used to analyze the correlation between RE and H. pylori infection. Results: A total of 359 cases of RE were detected. Excluding RE and other upper gastrointestinal organic diseases, 3 382 cases were considered as controls. Chi-square test showed that WS staining positive rate in RE group was significantly lower than that in control group (P=0.023), but there was no significant difference in the positive rate of H. pylori-IgG between the two groups (P=0.281). There were significant differences between RE group and control group in gender composition, age, body mass index (BMI), smoking, alcohol consumption, education level and mucosal active inflammation. Multivariate regression analysis showed that RE was negatively correlated with gastric mucosa active inflammation [OR=0.754 (95%CI 0.600-0.949), P=0.016], and positively correlated with male [OR=4.231 (95%CI 3.263-5.486), P<0.001], age ≥60 years, BMI≥24 kg/m2 [OR=1.540 (95%CI 1.220-1.945), P<0.001]. Compared to those aged 40-49 years and 50-59 years, the odds ratio (OR) of RE in these aged ≥60 years were 1.566 (95%CI 1.144-2.143, P=0.005) and 1.405 (95%CI 1.093-1.805, P=0.008). Conclusion: RE is more closely related to H. pylori present infection. Multivariate analysis showed that RE is negatively correlated with active inflammation of gastric mucosa caused by H. pylori infection, and positively correlated with male, overweight and aged ≥60 years.

[The risk of incident gastric cancer for populations with different precancerous gastric lesions: a prospective follow-up study].

Objective: To provide evidence for optimizing the screening strategy for gastric cancer (GC), we evaluated the risk of incident GC for individuals with different precancerous gastric lesions in a prospective cohort study. Methods: Based on the National Upper Gastrointestinal Cancer Early Detection Program launched in Linqu, Shandong, a high-risk area of gastric cancer in China, we included a total of 14 087 subjects diagnosed with different gastric lesions stages by endoscopic screening from 2012 to 2018. Study subjects were prospectively followed up until December 31, 2019. The incidence of GC during the follow-up was ascertained by repeated endoscopic examinations, cancer, death registry reports, and active follow-up of study subjects and was confirmed by reviewing medical records extracted from the hospital information management system. The Poisson regression model was applied to calculate the relative risk (RR) and 95%CI for GC occurrence among subjects with different gastric lesions. Results: Among 14 087 subjects with different gastric lesions as determined by their first endoscopic examination in 2012-2018, 7 608 (54.00%) had a global diagnosis of superficial gastritis (SG), 2 848 (20.22%) had chronic atrophic gastritis (CAG), 3 103 (22.03%) had intestinal metaplasia (IM), and 520 (3.69%) had low-grade intestinal neoplasia (LGIN). During the follow-up, 109 subjects were diagnosed with GC, including 63 with high-grade intestinal neoplasia (HGIN) and 46 with invasive GC. Compared to subjects having normal gastric mucosa or SG, those with CAG (RR=3.85, 95%CI: 2.04-7.28), IM (RR=5.18, 95%CI: 2.79-9.60), and LGIN (RR=19.08, 95%CI: 9.97-36.53) had significantly increased risk of progression to GC. Individuals with these gastric lesions had an elevated risk of developing HGIN and invasive GC. For subjects with LGIN, the RR was 22.96 (95%CI: 9.71-54.27) for developing HGIN and 14.64 (95%CI: 5.37-39.93) for developing invasive GC. Subgroup analyses found that all age group subjects with LGIN diagnosed during the initial endoscopic examination had a significantly increased risk of developing the GC. Conclusions: Our large-scale prospective study on a high-risk area of GC showed that most residents aged 40-69 years had gastric lesions of different stages. Subjects with more advanced gastric lesions had a significantly increased risk of progression to GC.

Association between serum creatinine level within normal range and bone mineral density in adolescents.

OBJECTIVE: The circulating level of creatinine is a direct, stable indicator of skeletal muscle mass. However, evidence regarding the correlation between serum creatinine (SCre) and bone health is limited. This study aimed to evaluate the association between SCre level within the normal range and bone mineral density (BMD) in adolescents. METHODS: We analyzed data for 3,395 adolescents aged 12-19 years from the National Health and Nutrition Examination Survey (2011-2018). Weighted multiple linear regression was conducted to assess the association between SCre and BMD. Weighted generalized additive models and smooth curve fittings were used to address nonlinearity. RESULTS: After controlling for potential confounding factors, we found that higher SCre levels were associated with higher total BMD and lumbar BMD in adolescents. This association remained positive in the subgroup analyses stratified by age, gender, or race. Furthermore, the positive association was more prominent in adolescent boys than adolescent girls aged 12-15 years. CONCLUSIONS: Our findings indicated that higher SCre levels within the normal range in adolescents aged 12-19 years were associated with higher BMD, suggesting that SCre may be a potential biomarker for bone health in adolescents.

Harmful algal bloom-related 311 calls, Cape Coral, Florida 2018-2019.

Harmful algal blooms (HABs) can adversely impact water quality and threaten human and animal health. People working or living along waterways with prolonged HAB contamination may face elevated toxin exposures and breathing complications. Monitoring HABs and potential adverse human health effects is notoriously difficult due to routes and levels of exposure that vary widely across time and space. This study examines the utility of 311 calls to enhance HAB surveillance and monitoring. The study focuses on Cape Coral, FL, USA, located along the banks of the Caloosahatchee River and Estuary and the Gulf of Mexico. The wider study area experienced a prolonged cyanobacteria bloom in 2018. The present study examines the relationship between weekly water quality characteristics (temperature, dissolved oxygen, pH, microcystin-LR) and municipal requests for information or services (algal 311 calls). Each 1 µg/L increase in waterborne microcystin-LR concentrations corresponded with 9% more algal 311 calls (95% confidence interval: 1.03-1.15, p = 0.002). The results suggest water quality monitoring and the 311 dispatch systems may be further integrated to improve public health surveillance.

[Sero-epidemiological characteristics of the hepatitis D virus infection among hepatitis B virus infected-patients at a single center in Xinjiang region].

Objective: To investigate the sero-epidemiological characteristics of the hepatitis D virus (HDV) infection among hepatitis B virus (HBV)-infected patients in Xinjiang region. Methods: A single-center cross-sectional analysis method was used to select 264 cases of hepatitis B virus infection who were hospitalized in the Center for Infectious Diseases and Liver Diseases of the First Affiliated Hospital of Xinjiang Medical University from August 2021 to January 2022. All patients were tested for HDV Ag, HDV IgM, HDV IgG, and HDV RNA. The infection status of hepatitis D virus was analyzed by grouping according to their clinical type, HBV viral load, and HBsAg level. A paired t-test was used for data with measurement data conforming to normal distribution. A paired rank sum test was used for data that did not conform to normal distribution before and after treatment. Results: A total of 36 cases (13.64%) and 26 cases (9.85%) were positive for HDV serological markers and HDV RNA. According to clinical type grouping, the positive rates of HDV serum markers in patients with chronic hepatitis B, hepatitis B-related cirrhosis, liver cancer, and liver failure were 13.46%, 12.43%, and 20.83%, respectively, and there was no statistically significant difference among the three groups (χ2=0.86, P=0.649). The positive rates of HDV RNA were 11.54%, 8.11%, and 20.83%, respectively, and there was no statistically significant difference among the three groups (χ2=4.015, P=0.134). According to HBV viral load grouping, the positive rates of HDV serum markers among patients with viral loads <20, 20-2 000, and >2 000 IU/ml were 17.15%, 7.81%, and 6.67%, respectively, and the difference was not statistically significant among the three groups (χ2=4.846, P=0.089). The positive rates of HDV RNA were 9.47%, 10.94%, and 10%, respectively, and the difference was not statistically significant among the three groups (χ2=0.113, P=0.945). According to HBsAg level grouping, the positive rates of HDV serum markers in HBsAg<0.05, 0.05~250, and >250 IU/ml were 14.29%, 16.67%, and 10.85%, respectively, and there was no statistically significance between the three groups (χ2=1.745, P=0.418). The positive rates of HDV RNA were 4.76%, 8.77%, and 11.63%, respectively, and there was no statistically significant difference among the three groups (χ2=1.221, P=0.543). Clinical outcome, disease course, HBV DNA, serological markers of viral hepatitis, routine blood test, biochemical indicators, coagulation function, and other laboratory indicators were compared between HDV serum marker and/or nucleic acid positive and negative patients, and there was no statistically significant difference (P>0.05). Conclusion: The positive rate of HDV serological markers and HDV RNA is 13.64% and 9.85%, respectively, at a single center in the Xinjiang region, and there is still a high HDV infection rate among the HBV-infected patients with low levels of viral load and HBsAg.

[Urine proteomics signatures associated with alcohol drinking among residents attending the National Upper Gastrointestinal Cancer Early Detection Program in Linqu, Shandong province].

The liquid chromatography tandem mass spectrometry was used to detect the urinary proteomics of 223 residents aged 40-69 years old who participated in the National Upper Gastrointestinal Cancer Early Detection Program in Linqu County, Shandong Province from November 22 to December 7, 2018, and analyze the alcohol consumption related proteomic profiles and individual urinary protein. There were significant differences in urinary protein profiles between alcohol consumption group and non-alcohol consumption group. The expression of 26 urinary proteins was up-regulated and 20 urinary proteins were down-regulated in alcohol consumption group (P<0.05). The differentially expressed proteins had enzyme inhibitor activity and phospholipid binding function, and mainly enriched in pathways involving proximal tubule bicarbonate regeneration, complement and coagulation cascade, and cholesterol metabolism. The protein expressions of complement factor I (CFI), angiotensin converting enzyme 2 (ACE2) and protein C inhibitor (SERPINA5) were positively correlated with daily alcohol consumption.

Untargeted analysis of first trimester serum to reveal biomarkers of pregnancy complications: a case-control discovery phase study.

Understanding of causal biology and predictive biomarkers are lacking for hypertensive disorders of pregnancy (HDP) and preterm birth (PTB). First-trimester serum specimens from 51 cases of HDP, including 18 cases of pre-eclampsia (PE) and 33 cases of gestational hypertension (GH); 53 cases of PTB; and 109 controls were obtained from the Global Alliance to Prevent Prematurity and Stillbirth repository. Metabotyping was conducted using liquid chromatography high resolution mass spectroscopy and nuclear magnetic resonance spectroscopy. Multivariable logistic regression was used to identify signals that differed between groups after controlling for confounders. Signals important to predicting HDP and PTB were matched to an in-house physical standards library and public databases. Pathway analysis was conducted using GeneGo MetaCore. Over 400 signals for endogenous and exogenous metabolites that differentiated cases and controls were identified or annotated, and models that included these signals produced substantial improvements in predictive power beyond models that only included known risk factors. Perturbations of the aminoacyl-tRNA biosynthesis, L-threonine, and renal secretion of organic electrolytes pathways were associated with both HDP and PTB, while pathways related to cholesterol transport and metabolism were associated with HDP. This untargeted metabolomics analysis identified signals and common pathways associated with pregnancy complications.

[Random survival forest: applying machine learning algorithm in survival analysis of biomedical data].

Traditional survival methods have a wide application in the field of biomedical research. However, applying traditional survival methods requires data to meet a set of special assumptions while the Random Survival Forest model can overcome this inconvenience. Herein, we used the clinical data of Primary Biliary Cholangitis (PBC) from Mayo Clinic to introduce and demonstrate Random Survival Forest model from mathematical principles, model building, practical example and attentions, aiming to provide a novel method for doing survival analysis.

Outcome of using vaginal misoprostol for treatment of retained products of conception after first trimester miscarriage: a retrospective cohort study.

PURPOSE: Standard treatment for retained products of conception (RPOC) is dilation and curettage (D&C), however, this brings a risk of intrauterine synechiae and subsequent fertility issues. A treatment strategy to avoid D&C is medical management with misoprostol. The justification for misoprostol in this setting is extrapolated from miscarriage and termination literature, however, no studies have looked specifically in the setting of RPOC. The purpose of this study is to determine the efficacy of misoprostol as definitive management of RPOC. MATERIALS AND METHODS: A retrospective cohort study was conducted from January 2016 to March 2017 at an Early Pregnancy Assessment Clinic. Patients diagnosed with RPOC with clinical symptoms and ultrasound findings of endometrial mass and/or doppler flow treated expectantly, medically with vaginal misoprostol or with a suction D&C underwent a chart review. Primary outcome was resolution of RPOC without surgical intervention. RESULTS AND CONCLUSIONS: Of 1743 unique pregnancies, 189 women were diagnosed with RPOC. 34% (65/178) chose misoprostol for management of RPOC. Baseline demographics between the three treatment modalities (expectant, medical, surgical) were comparable. 65% (42/65) of patients who took misoprostol avoided D&C. Misoprostol is most effective (76%) in the setting of RPOC if the primary treatment for miscarriage was expectant management, with less success with primary medical management (44%) and primary surgical management (40%).

Proteasomal degradation of the intrinsically disordered protein tau at single-residue resolution.

Intrinsically disordered proteins (IDPs) can be degraded in a ubiquitin-independent process by the 20S proteasome. Decline in 20S activity characterizes neurodegenerative diseases. Here, we examine 20S degradation of IDP tau, a protein that aggregates into insoluble deposits in Alzheimer's disease. We show that cleavage of tau by the 20S proteasome is most efficient within the aggregation-prone repeat region of tau and generates both short, aggregation-deficient peptides and two long fragments containing residues 1 to 251 and 1 to 218. Phosphorylation of tau by the non-proline-directed Ca2+/calmodulin-dependent protein kinase II inhibits degradation by the 20S proteasome. Phosphorylation of tau by GSK3ß, a major proline-directed tau kinase, modulates tau degradation kinetics in a residue-specific manner. The study provides detailed insights into the degradation products of tau generated by the 20S proteasome, the residue specificity of degradation, single-residue degradation kinetics, and their regulation by posttranslational modification.

[Technological innovation and patent transformation in rectal cancer surgery].

Surgery for rectal cancer has obtained quick improvement in techniques and concepts in recent years but still has challenging areas. Colorectal surgeons always seek to make operations clearer and easier, so that surgery can be safer and less time-consuming while guaranteeing surgical goals. With this purpose, our team have explored to make innovations in operations for rectal cancer and translate relevant patents from 2009. We summarize our achievements in this article as follows: (1) Reverse Miles operation (perineal operation first then laparoscopic abdominal operation) with two relevant patents-specialized instruments bag for laparoscopic operations (patent number ZL201520442331.0) and accessory spotlight for ultrasound scalpel (patent number ZL20102 0137689.X). (2) Laparoscopic sphincter-saving surgery for low rectal cancer through marker meeting approach with two patents-vacuum rectal drainage tube with functions of irrigation and ventilation (patent number ZL201520374385.8) and sterile sleeve cover of ultrasound scalpel handle (patent number ZL201920648102.2). (3) Laparoscopic radical resection of colorectal cancer and natural orifice specimen extraction. Different methods were designed according to the location of the tumor that classified as 20-40 cm, 10-20 cm and 5-10 cm to anus. Two relevant patents were specialized instruments for natural orifice specimen extraction (patent application number ZL2017101480141) and plastic film sleeve for natural orifice specimen extraction (patent application number ZL 201921169857.0). Reformation of surgical technique and innovation of surgical instruments should be conducted by surgeons with innovative thinking who always seek the way to translate ideas to patents and then real products to promote surgical treatment.

Fast and easy disinfection of coronavirus-contaminated face masks using ozone gas produced by a dielectric barrier discharge plasma generator

Face masks are one of the currently available options for preventing the transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has caused the 2019 pandemic. However, with the increasing demand for protection, face masks are becoming limited in stock, and the concerned individuals and healthcare workers from many countries are now facing the issue of the reuse of potentially contaminated masks. Although various technologies already exist for the sterilization of medical equipment, most of them are not applicable for eliminating virus from face masks. Thus, there is an urgent need to develop a fast and easy method of disinfecting contaminated face masks. In this study, using a human coronavirus (HCoV-229E) as a surrogate for SARS-CoV-2 contamination on face masks, we show that the virus loses its infectivity to a human cell line (MRC-5) when exposed for a short period of time (1 min) to ozone gas produced by a dielectric barrier discharge plasma generator. Scanning electron microscopy and particulate filtration efficiency (PFE) tests revealed that there was no structural or functional deterioration observed in the face masks even after they underwent excessive exposure to ozone (five 1-minute exposures). Interestingly, for face masks exposed to ozone gas for 5 min, the amplification of HCoV-229E RNA by reverse transcription polymerase chain reaction suggested a loss of infectivity under the effect of ozone, primarily owing to the damage caused to viral envelopes or envelope proteins. Ozone gas is a strong oxidizing agent with the ability to kill viruses on hard-to-reach surfaces, including the fabric structure of face masks. These results suggest that it may be possible to rapidly disinfect contaminated face masks using a plasma generator in a well-ventilated place.

Clinical outcomes of patients undergoing a cardiac implantable electronic device implantation following a recent non-device-related infection.

BACKGROUND: Clinical outcomes of patients undergoing a cardiac implantable electronic device (CIED) implantation following a recent non-device related infection are unknown. AIM: To evaluate the clinical outcomes of patients with recent infection before CIED implantation. METHODS: Consecutive patients (N = 1237) were classified as patients with recent infection (N = 72) and without recent infection (N = 1165). A recent infection was established by reviewing medical records, including symptoms and clinical manifestations, diagnosis of systemic inflammatory response syndrome, and quick Sequential Organ Failure Assessment (qSOFA) score. Multiple stepwise logistic regression analysis was used to identify independent predictors of in-hospital all-cause mortality. FINDINGS: During nearly three years of follow-up, 17 patients had CIED infection (1.4%), and the incidence of CIED infection did not significantly differ between patients with and without recent infection according to symptoms and clinical manifestations (2.8% vs 1.3%, respectively; not significant). However, patients with recent infection had a significantly higher in-hospital mortality rate compared to those without recent infection (22.2% vs 0.9%, respectively; P < 0.05). In multivariate analysis, predictors of in-hospital mortality were recent infection before CIED implantation (odds ratio: 20.3; 95% confidence interval: 8.4-49.3; P < 0.001) and end-stage renal disease (4.3; 1.4-12.8; P = 0.009). CONCLUSION: A CIED implantation is feasible in patients with recent infection if the patient is afebrile and has received an adequate duration of antibiotic therapy. Participants in shared decision-making before implant should be advised that recent infection increases in-hospital mortality risk, especially in patients with a qSOFA score of ≥2.